The present invention relates to novel peptides and methods of inhibiting tumor metastasis.
Selectins are cell-surface carbohydrate binding proteins that mediate cell adhesion between leukocytes and the vascular endothelial surface. For example, binding of E-selectin to its ligand expressed on the surface of circulating neutrophils initiates rolling, and an early step in the recruitment of these cells to a site of injury or inflammation. Several potential therapeutics have been tested for their ability to inhibit adhesion of E-selectin to neutrophils, including carbohydrate-based molecules, antibodies, soluble E-selectin, and selectin-Ig chimeras. While these molecules have been useful to show the utility of selectin blockers for treating inflammation, each has significant shortcomings as a therapeutic, including short in vivo half-life, potential immunogenicity, high cost, and other side effects. A further drawback of these approaches is the lack of an efficient means to improve the pharmaceutical properties of these various molecules.
Cancer is a leading cause of death in developing countries. It is known that metastatic spread of cancer cells can not be prevented by surgery. Growing evidence suggests that carbohydrate-mediated cancer cell adhesion to selectins on the vascular endothelium is involved in the metastasis of a wide variety of epithelial cancers, including gastric, colorectal, pancreatic, liver, ovary, head and neck, and breast cancers. However, methods of effectively inhibiting carbohydrate-mediated cancer cell adhesion to selectins on the vascular endothelium are lacking.
Recent advances in methods for the preparation and screening of large numbers of individual peptides has led to the identification of numerous peptides useful in all areas of biomedical research, including research regarding the interaction of ligands to cell surface molecules. Even with these advances, however, compounds that effectively inhibit tumor metastasis are lacking. Thus, a need exists for compounds useful to treat cancer by inhibiting metastasis. This invention satisfies these needs and provides related advantages as well.
In accordance with the present invention, there are provided peptides that bind to a member of the mammalian selectin family and inhibit the binding of a carbohydrate to said selectin. Invention peptides are useful to inhibit of the adhesion of cells containing particular cell-surface carbohydrates to cells containing cell-surface selectins.
Also provided in accordance with the present invention are pharmaceutical compositions comprising invention peptides useful in methods for inhibiting a carbohydrate from binding to a selectin, and in methods of inhibiting tumor cell metastasis and inflammation in a subject.